PRAP1 is a novel lipid-binding protein that promotes lipid absorption by facilitating MTTP-mediated lipid transport.
PRAP1 is a novel lipid-binding protein that promotes lipid absorption by facilitating MTTP-mediated lipid transport.
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DOI：
10.1074/jbc.ra120.015002
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Yang-Yen HF
中科院分区：
文献类型：
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作者：
Peng H;Chiu TY;Liang YJ;Lee CJ;Liu CS;Suen CS;Yen JJ;Chen HT;Hwang MJ;Hussain MM;Yang HC;Yang-Yen HF
微粒体甘油三酯转移蛋白（MTTP）是一种内质网驻留蛋白，对于富含甘油三酯（TG）、含载脂蛋白B的脂蛋白的组装和分泌至关重要。虽然哺乳动物MTTP的功能和结构已被广泛研究，但MTTP如何将脂质转移到脂质受体以及是否有其他生物分子参与MTTP介导的脂质转运仍然是难以捉摸的。在这里，我们确定了一个角色，在这个过程中的不良特征的蛋白质PRAP 1。我们报告，PRAP 1和MTTP部分共定位在内质网。我们观察到PRAP 1直接结合TG并促进MTP介导的脂质转移。位置85（E85 V）处的单个氨基酸突变损害PRAP 1与TG和MTTP形成三元复合物的能力，以及损害其促进MTTP介导的含apoB的脂蛋白组装和分泌的能力，这表明三元复合物的形成是PRAP 1促进MTTP介导的脂质转运所必需的。PRAP 1在乳糜微粒/VLDL富集的血浆组分中可检测到，表明MTTP将PRAP 1结合的TG识别为货物，并将TG沿着PRAP 1转移至脂质受体。PRAP 1缺陷和E85 V基因敲入突变小鼠在喂食普通饲料后，小肠长度都有所增加，这可能是为了弥补吸收脂质的挑战。有趣的是，与同窝对照组相比，这两种转基因小鼠在高脂肪饮食中体重和脂肪量明显减少，并防止了脂肪肝。总之，这项研究提供了证据表明，PRAP 1在MTP介导的脂质转运和脂质吸收中起着重要作用。
Microsomal triglyceride transfer protein (MTTP) is an endoplasmic reticulum resident protein that is essential for the assembly and secretion of triglyceride (TG)-rich, apoB-containing lipoproteins. Although the function and structure of mammalian MTTP have been extensively studied, how exactly MTTP transfers lipids to lipid acceptors and whether there are other biomolecules involved in MTTP-mediated lipid transport remain elusive. Here we identify a role in this process for the poorly characterized protein PRAP1. We report that PRAP1 and MTTP are partially colocalized in the endoplasmic reticulum. We observe that PRAP1 directly binds to TG and facilitates MTTP-mediated lipid transfer. A single amino acid mutation at position 85 (E85V) impairs PRAP1's ability to form a ternary complex with TG and MTTP, as well as impairs its ability to facilitate MTTP-mediated apoB-containing lipoprotein assembly and secretion, suggesting that the ternary complex formation is required for PRAP1 to facilitate MTTP-mediated lipid transport. PRAP1 is detectable in chylomicron/VLDL-rich plasma fractions, suggesting that MTTP recognizes PRAP1-bound TG as a cargo and transfers TG along with PRAP1 to lipid acceptors. Both PRAP1-deficient and E85V knock-in mutant mice fed a chow diet manifested an increase in the length of their small intestines, likely to compensate for challenges in absorbing lipid. Interestingly, both genetically modified mice gained significantly less body weight and fat mass when on high-fat diets compared with littermate controls and were prevented from hepatosteatosis. Together, this study provides evidence that PRAP1 plays an important role in MTTP-mediated lipid transport and lipid absorption.